Neuromuscular fatigue, defined as an acute decline in the force capacity of the neuromuscular system brought about by muscular activity, is a prevalent phenomenon. Fatigue is encountered in daily activities and in the workplace, it is a debilitating factor in a number of neuromuscular diseases including muscular dystrophy, myasthenia gravis, and multiple sclerosis, it has been implicated as a contributor to neonatal respiratory failure, and it seriously impedes the re-animation of paralyzed muscle by functional electrical stimulation. Although it is generally well-accepted that fatigue is caused, in part, by impairment of processes within muscle, the role played by the nervous system in fatigue remains controversial. Adjustments in neural behavior during prolonged activity are believed to slow the rate of force loss by optimizing the input to muscle as its mechanical function alters. Conversely, it has been suggested that the nervous system contributes to force decline by failing to adequately excite muscle during prolonged activity. The disparity of views likely stems from 1) differences in the paradigms used to induce fatigue and 2) the treatment of muscle as a homogenous entity rather than as a system comprised of a diverse population of motor units. The broad goal of the proposed research is to determine if the nervous system contributes to force-loss during fatigue in human subjects by examining the adaptations in mechanical, electrical and neural function of single motor units during different types of prolonged activity. One specific aim is to quantify the changes in contractile and myoelectric properties of different motor units following voluntary fatigue protocols. This will be accomplished by recording force and EMG responses to different rates of intraneural stimulation of single motor axons innervating intrinsic hand muscles before and immediately after various fatigue tasks (sustained/intermittent, submaximal/maximal). A second aim is to document the adaptations in the discharge behavior of motor units during the same type of fatigue protocols used in the first aim. Alterations in discharge rate and variability will be determined from long trains of motor unit action potentials recorded with intramuscular tungsten microelectrodes. A third aim is to determine how the pattern of neural activity influences motor unit fatigue. A new technique will be employed to activate the same motor unit on separate days with stimulus protocols that will vary only in the pattern (continuous/intermittent, constant/random interstimulus intervals) but not number of stimuli delivered. The fourth specific aim is to compare the force-decline in muscle activated with a stimulus-rate pattern that mimics the reduction in motor unit discharge during voluntary contraction to that i which the stimulus rate is maintained constant. The results of these experiments should help elucidate whether adaptation of motor unit activity during prolonged muscle contraction protects against or contributes to fatigue.